Anti-receptor antibodies produced against monoclonal anti-H-2 antibodies do not appear to detect determinants on alloreactive T cells. One possible explanation is that T cells and B cells do not recognize the same allodeterminants on Class I molecules. Therefore, current efforts have been devoted to examining the nature of the allo-determinants recognized by cloned T cell populations as compared to those determinants recognized by alloantibodies. To examine this question, H-2 structural mutants have been isolated from a somatic cell line by mutagenesis and immunoselection using monoclonal anti-H-2 antibodies. Examination of alloantigen-specific CTL clones on these mutants suggest that the majority of CTL clones recognize determinants different from those which elicit antibody production. In addition, the regions of the MHC molecule involved in CTL recognition were studied using L cells transfected with H-2 genes constructed by shuffling exons between the H-2Kb and Db genes. The findings suggest that unlike mAbs which can recognize individual epitopes on different domains, CTL recognition is influenced by the interaction of the two external domains.